Bioscar

OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multi-criterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least one episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (ie, synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy CT, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSIONS: The new classification criteria, developed using a data-driven and decision-analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.

OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSION: The new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.

BACKGROUND: Given the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA. METHODS: Using a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls. RESULTS: ). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone. CONCLUSIONS: We found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Substantial evidence suggests that chronic hyperuricemia is an independent risk factor for hypertension, metabolic syndrome, chronic kidney disease (CKD) and cardiovascular diseases. This highlights the need for greater attention to serum uric acid levels when profiling patients, and suggests that the threshold above which uricemia is considered abnormal is 6 mg/dl, in light of the available evidence. Another important question is whether lowering serum uric acid can improve cardiovascular and renal outcomes, and what therapeutic mechanism of action could provide more clinical benefits to patients; the available literature shows a trend toward improvement associated with administration of urate-lowering drugs, in particular for the xanthine oxidase inhibitors. The demonstrated efficacy of urate-lowering therapy on outcomes other than gout flares leads to the consideration that treatment may be beneficial even in the absence of overt gout when hyperuricemia accompanies other clinical conditions, such as urate deposition, advanced CKD or cardiovascular risk factors.

Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

The effects of a second generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB 239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridim idi n-4-yl)imidazole; IC(50) = 44 nM vs. p38 alpha], were assessed in models that represent different pathological aspects of chronic obstructive pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine formation and increased matrix metalloproteinase (MMP)-9 activity] and in a model of lung fibrosis. Airway neutrophil infiltration and interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h after lipopolysaccharide (LPS) inhalation, were inhibited dose dependently by 3-30 mg/kg of SB 239063 given orally twice a day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6 bronchoalveolar lavage fluid concentrations (>90% inhibition) and MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure. In guinea pig cultured alveolar macrophages, SB 239063 inhibited LPS-induced IL-6 production (IC(50) of 362 nM). In a bleomycin-induced pulmonary fibrosis model in rats, treatment with SB 239063 (2.4 or 4.8 mg/day via osmotic pump) significantly inhibited bleomycin-induced right ventricular hypertrophy (indicative of secondary pulmonary hypertension) and increases in lung hydroxyproline synthesis (indicative of collagen synthesis and fibrosis). Therefore, SB 239063 demonstrates activity against a range of sequelae commonly associated with COPD and fibrosis, supporting the therapeutic potential of p38 MAPK inhibitors such as SB 239063 in chronic airway disease.

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls. Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT , RTEL1 , PARN or SFTPC coding regions . The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT , RTEL1 , PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53–6.12; p=9.45×10 −4 ). Telomeres were shorter in RA-ILD patients with a TERT , RTEL1 or PARN mutation than in controls (p=2.87×10 −2 ). Our results support the contribution of FPF-linked genes to RA-ILD susceptibility.

Breast cancer is the most common type of cancer worldwide and one of the major causes of cancer death in women. Epidemiological studies have established a link between night-shift work and increased cancer risk, suggesting that circadian disruption may play a role in carcinogenesis. Here, we aim to shed light on the effect of chronic jetlag (JL) on mammary tumour development. To do this, we use a mouse model of spontaneous mammary tumourigenesis and subject it to chronic circadian disruption. We observe that circadian disruption significantly increases cancer-cell dissemination and lung metastasis. It also enhances the stemness and tumour-initiating potential of tumour cells and creates an immunosuppressive shift in the tumour microenvironment. Finally, our results suggest that the use of a CXCR2 inhibitor could correct the effect of JL on cancer-cell dissemination and metastasis. Altogether, our data provide a conceptual framework to better understand and manage the effects of chronic circadian disruption on breast cancer progression.

OBJECTIVE: There is no curative treatment for osteoarthritis (OA), which is the most common form of arthritis. This study was undertaken to identify causal risk factors of knee, hip, and hand OA. METHODS: Individual-level data from 384,838 unrelated participants in the UK Biobank study were analyzed. Mendelian randomization (MR) analyses were performed to test for causality for body mass index (BMI), bone mineral density (BMD), serum high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglyceride levels, type 2 diabetes, systolic blood pressure (BP), and C-reactive protein (CRP) levels. The primary outcome measure was OA determined using hospital diagnoses (all sites, n = 48,431; knee, n = 19,727; hip, n = 11,875; hand, n = 2,330). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. RESULTS: MR analyses demonstrated a robust causal association of genetically determined BMI with all OA (OR per SD increase 1.57 [95% CI 1.44-1.71]), and with knee OA and hip OA, but not with hand OA. Increased genetically determined femoral neck BMD was causally associated with all OA (OR per SD increase 1.14 [95% CI 1.06-1.22]), knee OA, and hip OA. Low systolic BP was causally associated with all OA (OR per SD decrease 1.55 [95% CI 1.29-1.87]), knee OA, and hip OA. There was no evidence of causality for the other tested metabolic factors or CRP level. CONCLUSION: Our findings indicate that BMI exerts a major causal effect on the risk of OA at weight-bearing joints, but not at the hand. Evidence of causality of all OA, knee OA, and hip OA was also observed for high femoral neck BMD and low systolic BP. However, we found no evidence of causality for other metabolic factors or CRP level.

This review article summarizes the relevant English literature on gout from 2010 through April 2017. It emphasizes that the current epidemiology of gout indicates a rising prevalence worldwide, not only in Western countries but also in Southeast Asia, in close relationship with the obesity and metabolic syndrome epidemics. New pathogenic mechanisms of chronic hyperuricaemia focus on the gut (microbiota, ABCG2 expression) after the kidney. Cardiovascular and renal comorbidities are the key points to consider in terms of management. New imaging tools are available, including US with key features and dual-energy CT rendering it able to reveal deposits of urate crystals. These deposits are now included in new diagnostic and classification criteria. Overall, half of the patients with gout are readily treated with allopurinol, the recommended xanthine oxidase inhibitor (XOI), with prophylaxis for flares with low-dose daily colchicine. The main management issues are related to patient adherence, because gout patients have the lowest rate of medication possession ratio at 1 year, but they also include clinical inertia by physicians, meaning XOI dosage is not titrated according to regular serum uric acid level measurements for targeting serum uric acid levels for uncomplicated (6.0 mg/dl) and complicated gout, or the British Society for Rheumatology recommended target (5.0 mg/dl). Difficult-to-treat gout encompasses polyarticular flares, and mostly patients with comorbidities, renal or heart failure, leading to contraindications or side effects of standard-of-care drugs (colchicine, NSAIDs, oral steroids) for flares; and tophaceous and/or destructive arthropathies, leading to switching between XOIs (febuxostat) or to combining XOI and uricosurics.

OBJECTIVE: To determine which clinical, laboratory, and imaging features most accurately distinguished gout from non-gout. METHODS: We performed a cross-sectional study of consecutive rheumatology clinic patients with ≥1 swollen joint or subcutaneous tophus. Gout was defined by synovial fluid or tophus aspirate microscopy by certified examiners in all patients. The sample was randomly divided into a model development (two-thirds) and test sample (one-third). Univariate and multivariate association between clinical features and monosodium urate-defined gout was determined using logistic regression modeling. Shrinkage of regression weights was performed to prevent overfitting of the final model. Latent class analysis was conducted to identify patterns of joint involvement. RESULTS: In total, 983 patients were included. Gout was present in 509 (52%). In the development sample (n = 653), the following features were selected for the final model: joint erythema (multivariate odds ratio [OR] 2.13), difficulty walking (multivariate OR 7.34), time to maximal pain <24 hours (multivariate OR 1.32), resolution by 2 weeks (multivariate OR 3.58), tophus (multivariate OR 7.29), first metatarsophalangeal (MTP1) joint ever involved (multivariate OR 2.30), location of currently tender joints in other foot/ankle (multivariate OR 2.28) or MTP1 joint (multivariate OR 2.82), serum urate level >6 mg/dl (0.36 mmoles/liter; multivariate OR 3.35), ultrasound double contour sign (multivariate OR 7.23), and radiograph erosion or cyst (multivariate OR 2.49). The final model performed adequately in the test set, with no evidence of misfit, high discrimination, and predictive ability. MTP1 joint involvement was the most common joint pattern (39.4%) in gout cases. CONCLUSION: Ten key discriminating features have been identified for further evaluation for new gout classification criteria. Ultrasound findings and degree of uricemia add discriminating value, and will significantly contribute to more accurate classification criteria.

Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuroimmune communications mediated by dopamine. Studies of dendritic cells (DCs) revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs). Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4(+) T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS) and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis (RA). The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or RA. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.

Knee osteoarthritis (KOA) is a chronic disorder characterized by joint pain, increasing physical disability, and progressive cartilage degeneration, which can lead to total knee arthroplasty (TKA). Despite extensive research, the complex pathophysiology of KOA remains incompletely understood. As a result, no established disease-modifying treatment exists today, and the management of KOA still relies on a combination of nonpharmacologic and pharmacologic modalities 1 primarily intended to relieve the symptoms of pain and loss of knee function. In clinical practice, acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs) are generally recommended to relieve pain and improve joint function 2-5. However, due to their vascular and gastrointestinal toxicity 6, 7, the risk-benefit ratio of these rapid-acting drugs might not be favorable, particularly for long-course therapies and within the aging population in which KOA is most prevalent 8. Intraarticular (IA) injections of corticosteroids such as triamcinolone hexacetonide and methylprednisolone acetate are also commonly prescribed. As a systemic absorption occurs following IA corticosteroid injection, systemic adverse events (AEs) can be expected and precautions should be observed in patients with concomitant diseases such as hypertension or diabetes mellitus 9-13. IA hyaluronic acid (HA) is a local treatment modality devoid of the systemic AEs observed after IA corticosteroid injection or oral administration of analgesics and NSAIDs. Thus, IAHA represents an alternative to analgesics and NSAIDs in patients with comorbidities, as well as a secondary option in case of inadequate response to first-line pharmacologic KOA treatments 14. Registered as medical devices in the US, IAHA preparations are currently approved for the symptomatic treatment of KOA, one of the most commonly affected joints. Despite being widely employed in the daily management of KOA for almost 20 years in the US (about 30 years in Europe and Japan), controversies persist regarding their efficacy and safety, as highlighted by discrepancies in the guidelines related to the use of IAHA in clinical practice 2-5, 15, which largely reflect the divergent conclusions drawn by meta-analyses on the topic 16-30. For this purpose, the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) convened an international task force of experts in OA and clinical research methodology. Seven members of this working group (CC, FR, PR, OB, GH-B, AM, and DU) were entrusted with the task of preparing a review on diverse aspects of the use of IAHA in the management of KOA. Current knowledge on the mode of action, efficacy, effectiveness, safety, and cost-effectiveness of this treatment modality was presented and discussed at a 1-day meeting in January 2016 in Geneva (Switzerland). The objective of this review is to provide specialists and practicing physicians with clear, concise, and reasoned answers to questions they might have on the use of IAHA in the management of KOA. Efficacy of IAHA on pain and joint function has been evaluated in numerous randomized controlled trials (RCTs). Consequently, 15 meta-analyses/systematic reviews assessing the symptomatic effects of IAHA on KOA have been published to date 16-30. Six of them concluded on a clear efficacy of IAHA 17, 20, 24, 27, 29, 30, 4 considered it as a marginally efficacious treatment modality 16, 19, 25, 26, and 2 meta-analyses found no significant difference in efficacy between IAHA and IA placebo 18, 21 (Table 1). The reported effect sizes (ES) for pain favored IAHA over IA placebo and ranged from 0.20 (30) to 0.46 (24). Heterogeneity of outcomes between trials was relatively high in several meta-analyses 16, 20, 24, 27. As shown by Bannuru et al, the benefits of IAHA vary over time, with a maximal effect on pain at 8 weeks (ES 0.46 [95% confidence interval (95% CI) 0.28, 0.65]) that is still observable at 24 weeks (ES 0.21 [95% CI 0.10, 0.31]) 24. This time dependency may partly contribute to the differences in pain estimates that have been observed between meta-analyses. Another possible explanation is the inclusion of clinical trials that widely differ in methodological quality. Thus, when the analysis was restricted to high-quality trials, an ES of 0.34 (95% CI 0.02, 0.67) and of 0.20 (95% CI 0.03, 0.37) in favor of IAHA was obtained at 8 and 24 weeks, respectively 24. These results were confirmed by Richette et al, who examined clinical data obtained from IA placebo controlled trials with a low risk of bias only (n = 8) in order to reach the highest level of evidence. Based on an ES of 0.20 (95% CI 0.12, 0.29) for pain at 12 weeks, the authors concluded that IAHA provided a moderate but real effect on pain in patients with KOA 30. Since the estimates for pain mentioned above were based on the difference between the IA placebo and the IAHA effects, it is worth noting that evidence for a clinically significant response of the IA delivery method itself has recently been demonstrated in a meta-analysis, with an ES of 0.29 (95% credible interval [95% CrI] 0.04, 0.54) in favor of IA placebo compared with oral placebo 29. In the same study, different treatment options of KOA were compared based on their ES versus oral placebo at 3 months. IAHA was found to be the most efficacious intervention with an ES of 0.63 (95% CrI 0.39, 0.88), followed by IA corticosteroids (ES 0.61 [95% CrI 0.32, 0.89]), diclofenac (ES 0.52 [95% CrI 0.34, 0.69]), ibuprofen (ES 0.44 [95% CrI 0.25, 0.63]), naproxen (ES 0.38 [95% CrI 0.27, 0.49]), celecoxib (ES 0.33 [95% CrI 0.25, 0.42]), and IA placebo. With an ES of 0.18 (95% CrI 0.04, 0.33), acetaminophen was considered as not superior to oral placebo in relieving pain 29. In direct comparison, IAHA was shown to be not significantly different from continuous oral NSAID treatment at 4 and 12 weeks regarding pain, function, and stiffness 28, and superior to IA corticosteroids from 8 to 26 weeks regarding pain 23. The extent to which IAHA achieves its intended effect in the “real-life” clinical setting cannot be measured in RCTs, since patients in such studies are not representative of those seen in usual practice. Therefore, observational studies of real practice are better suited in evaluating effectiveness of IAHA. Petrella and Wakeford retrospectively assessed the effectiveness of IA crosslinked HA (hylan) using the Southwestern Ontario database, a Canadian real-world cohort 31. For this purpose, they identified 1,263 patients with OA in 1 or both knees that received 2 consecutive series of IA hylan injections and no other prescribed OA medications. They compared them to a cohort of 3,318 demographically matched KOA patients who were never treated with IAHA. All patients were evaluated fully between 2006 and 2012. Results showed that in the group of patients who received repeated treatments of IA hylan, pain at rest and pain after a 6-minute walk decreased by mean ± SD 3.7 ± 1.8 points and 5.6 ± 1.7 points on a 10-point visual analog scale, respectively. In parallel, the distance walked in a 6-minute walk test increased on average by 115 meters in this patient group. These improvements in pain and physical function were significantly greater than those achieved in KOA-matched patients treated with other prescribed OA medications (intergroup comparison P < 0.012 for pain at rest, P < 0.001 for pain after a 6-minute walk, and P < 0.001 for distance walked in a 6-minute walk test). Previous observational studies already found that IAHA was effective in relieving pain and improving knee function for up to 6 months 32-34. Such pragmatic trials were also adapted in the assessment of longer-term outcomes. Three recent retrospective studies examined the time from diagnosis of KOA to TKA and whether this time would be influenced by the use of IAHA 35-37. Large populations of insured subjects were screened and about 250,000 TKAs were reviewed after exclusions. In these studies, the median time to arthroplasty from the index time of KOA diagnosis was 114, 86, and 326 days in those not receiving IAHA. The median time from diagnosis to TKA in those receiving IAHA was 484, 585, and 908 days. Two studies including 65-year-old subjects showed a 1-year increase in time to surgery 35, 36. The study including only those younger than age 65 years showed an increase in time to surgery of 1.6 years 37. All studies showed increased time to surgery with increased series of IAHA, and 2 studies suggested additional benefit from higher molecular weight (MW) HA products 36, 37. The consistency of results from the 3 studies suggests both clinical and economic benefits to IAHA. However, they are insufficient to prove that the observed delay in time to TKA results from the use of IAHA, as treatment was not allocated randomly. Thus, between-group differences might reflect a bias in patient selection. As the evidence for efficacy of IAHA on knee pain and function is currently established, the ESCEO task force suggests promoting pragmatic trials in order to focus clinical research on the effectiveness of IAHA in real-life conditions, considering the patient situation in terms of individual and disease characteristics, medical history, and comorbidities. Seven meta-analyses of RCTs comparing IAHA to IA placebo evaluated the safety of the intervention 17, 18, 20, 21, 26, 27, 29. AEs occurred slightly more often among patients who received an IAHA treatment (relative risk [RR] 1.08 [95% CI 1.01, 1.15]) 18. However, they were usually mild transient local reactions such as pain at the injection site and swelling, with an RR of 1.19 (95% CI 1.01, 1.41) according to Wang et al 17 or RR 1.34 (95% CI 1.13, 1.60) according to Rutjes et al 26. The use of IAHA has also been associated with increased risk of flares (RR 1.51 [95% CI 0.84, 2.72]) and effusion at the injected knee (RR 1.15 [95% CI 0.38, 3.54]), which were not statistically significant 26. In contrast, the meta-analysis of US-approved HA products by Miller and Block reported no statistically significant differences between IAHA and IA placebo for any safety outcomes, including serious AEs (P = 0.12), treatment-related serious AEs (P = 1.0), study withdrawal (P = 1.0), and AE-related study withdrawal (P = 0.46) 27. Only Rutjes et al raised concerns about the safety of IAHA. Their meta-analysis emphasized an increased risk of serious AEs (RR 1.41 [95% CI 1.02, 1.97]) and dropouts due to AEs (RR 1.33 [95% CI 1.01, 1.74]). However, these findings have been criticized regarding the methodological rigor with which the serious AEs were analyzed and the biologic plausibility of the reported events 38, 39. As shown in a review by Pagnano and Westrich 40, the safety of IAHA appears to remain unchanged with multiple courses of treatment, while there might be an increase in AEs after the first hylan injection(s). Leopold et al reported that patients receiving multiple cycles of IA hylan exhibited more than an 8-fold increase in the frequency of acute local reactions compared with patients receiving only 1 course 41. In addition to the AEs mentioned above, postmarketing device surveillance highlighted the occurrence of rare cases of localized inflammatory reactions such as pseudosepsis/severe acute inflammatory reactions, predominantly reported after avian high-MW crosslinked HA injections (hylan) 42. In comparison with other pharmacologic interventions for the treatment of KOA, IAHA therapy was shown to exhibit fewer systemic AEs than acetaminophen or oral NSAIDs, but more local reactions 43. These events were reported to be similar between different IA therapies, i.e., HA and corticosteroids. Withdrawals due to AEs were more common among patients receiving acetaminophen or NSAIDs than IA therapies 29. As a result, after almost 30 years of use, IAHA is usually recognized as a safe treatment modality for KOA. As shown in the previous sections dealing with the efficacy, effectiveness, and safety of IAHA, there is increasing evidence that the risk-benefit balance is favorable to the use of IAHA in the management of KOA 24, 26, 27, 29, 30, 44. However, while IAHA was initially clearly recommended by national and international professional societies, such as the Osteoarthritis Research Society International (OARSI) 45, the European League Against Rheumatism (EULAR) 2, and the American College of Rheumatology (ACR) 46, some clinicians, researchers, and decision makers feel that current guidelines are conflicting and less favorable than 10 years ago 47, 48. Nevertheless, there is relative general agreement on the place of IAHA in the management of KOA across organizations (Table 2). Apart from the American Academy of Orthopedic Surgeons, which refutes the use of IAHA based on insufficient clinical efficacy compared with IA saline 15, and the National Institute for Health and Care Excellence, which does not assess the modality at all 5, the use of IAHA is recommended as second-line treatment of KOA (Table 2). Organization (issue date) Based on the available evidence and guidelines, the ESCEO recommends using IAHA in patients remaining symptomatic despite continuous or intermittent treatment with conventional pharmacologic treatment modalities, i.e., acetaminophen, symptomatic slow-acting drugs, and NSAIDs, as well as in patients with comorbidities precluding the use of NSAIDs. This positioning is clearly highlighted in the ESCEO treatment algorithm for the management of KOA and may help the prescribing physician prioritize interventions 14, 49. The ACR guidelines move in the same direction and present IAHA as an alternative to unsatisfactory initial pharmacologic therapy 46. Furthermore, they emphasize its particular interest for patients ages >75 years, who are not recommended to take oral NSAIDs 4, 14. EULAR considers the use of IAHA for pain relief and knee functional improvement based on level 1B evidence 2. OARSI guidelines for the nonsurgical management of KOA probably raise the most considerable amount of misunderstanding. However, as clearly stated in the main part of the article, an “uncertain” classification was “…not intended to be a negative recommendation or preclude use of that therapy. Rather it indicates a role for physician-patient interaction in determining whether this treatment may have merit in the context of its risk: benefit profile and the individual characteristics, co-morbidities, and preferences of the patient” 3. In other words, OARSI privileges the use of IAHA for specific clinical phenotypes, which should be defined by the prescribing physician. Finally, as recently highlighted by Altman et al 50, clinical practice guidelines, and a fortiori recommendations for the use of IAHA in the management of KOA, are not intended to create uniformity and suppress treating physicians' self-analysis of the patient situation; they are designed to provide the best evidence-based information available to help physicians in making a treatment decision. In the US, from a purely regulatory point of view, the symptomatic effects of most of the IAHA preparations are considered to primarily result from the unique properties of HA in solution; when injected intraarticularly, exogenous HA is able to compensate for the drop in HA concentration and chain length that has been observed during the progression of OA, thus restoring the elastic and viscous properties of the synovial fluid, which are responsible for its resistance to compression and its lubricating effect, respectively 51, 52. However, these direct mechanical effects of exogenous HA cannot account for its long-term benefits observed in clinical trials 24, as it is cleared from the joint within a few days, depending on the IAHA preparation. the 30 years, several possible pharmacologic of the clinical effects of IAHA persist for several months have been recent review of the by Altman et al highlighted the role of HA to of in this complex as numerous of its effects of and and in contribute to the and effects as observed in HA to 1 and of transient 1 have also been In the has been suggested to contribute to the antiinflammatory and of of effects of IAHA in joint there is evidence that HA that are in the OA joint can inflammatory or exogenous HA is injected in the the of these is thus The ESCEO group is not that one mode of is to the of IAHA and the that several and to relieve OA Furthermore, in results obtained on may not be the same as clinically in an it and to to patients with a low level of This in daily clinical practice has been in the of study a in patients with symptomatic KOA who received 4 consecutive cycles IA of HA of or placebo. were at 6 months after the first and cycles and at 12 months after the and in a total study of months. the of the study, the according to the in response was significantly higher in the IAHA group than in the group versus RR [95% CI P = the of to IAHA increased after treatment while response to IA placebo with a statistically significant between-group difference from 1 (P < increase in AEs occurred with repeated cycles of IAHA. Based on these the ESCEO task force the use of repeated cycles of IAHA in patients who to the first injection, a treatment as as the first symptoms are more than IAHA preparations They differ in characteristics, including versus mean and molecular and a of method of concentration of injection and of the preparations different of such as or of these may have an on the effect of the IAHA treatment, research has on the differences from the of For this purpose, the exogenous HA available for IA injections are 3 low and high including crosslinked of HA The for an of the results from research on the mode of of IAHA. as in the review by Altman et al showed that higher may provide superior and these differences observed in clinical evidence is not clearly established Two meta-analyses comparing different IAHA preparations have been published to date (Table 1). The first one compared hylan with IAHA and found no clinically benefits in terms of efficacy of of preparation. However, the for local AEs (RR [95% CI = and flares (RR [95% CI = were observed to be as high with hylan than with or HA In a higher of cases were reported with hylan than with other IAHA risk might increase with courses In the meta-analysis, comparing different available IAHA the authors were not able to that one a better efficacy than due to the of the studies and outcomes In most RCTs to date have found with to symptomatic efficacy between the HA preparations evaluated only 1 was able to a statistically significant difference between 2 IAHA preparations in regarding symptomatic this study in patients with KOA showed that an HA provided statistically superior pain relief at 6 months than a points confirmed the Based on the above, the ESCEO task force considers that there is currently no clinical evidence an in efficacy of one over Furthermore, properties of particular IAHA preparations provide results in comparison with other IAHA related to the patient are to Only studies evaluating the cost-effectiveness of IAHA have been published to date (Table of them were in patients with KOA who received IA injections of hylan data are in favor of IAHA, only a few or were based on Furthermore, some were not such as those associated with Therefore, the ESCEO task force recommends more in the and comparison of the and benefits of IAHA in the management of KOA. This review aspects related to the use of IAHA in the management of KOA. its safety profile and its moderate but real efficacy on which is in the same as other pharmacologic treatment modalities in this The effectiveness of IAHA has also been highlighted based on real-life clinical data and should be to when making to individual patient The ESCEO working group is that IAHA is not a for treating a disease such as KOA. However, KOA is to the and with significant comorbidities, the use of several conventional options such as acetaminophen, NSAIDs, or Therefore, the experts convened by the ESCEO feel that the medical cannot to the use of IAHA, particularly that treatment cycles have been shown to results in terms of both efficacy and they that IAHA is a alternative in patients with KOA who have not to previous pharmacologic and a in the for KOA in patients with to conventional The ESCEO task force for additional clinical trials cohort to the patient phenotypes, treatment associated with an risk-benefit Such research may help in determining that may take most of IAHA. All authors were in the or it for and all authors approved the to be for to all of the data in the study and for the of the data and the of the data is an of International

Nitric oxide (NO) is implicated in a number of inflammatory processes and is an important mediator in animal models of rheumatoid arthritis and in in vitro models of cartilage degradation. The pyridinyl imidazole SB 203580 inhibits p38 mitogen-activated protein (MAP) kinase in vitro, blocks proinflammatory cytokine production in vitro and in vivo, and is effective in animal models of arthritis. The purpose of this study was to determine whether SB 203580 could inhibit p38 MAP kinase activity, NO production, and inducible NO synthase (iNOS) in IL-1 stimulated bovine articular cartilage/chondrocyte cultures. The results indicated that SB 203580 inhibited both IL-1 stimulated p38 MAP kinase activity in isolated chondrocytes and NO production in bovine chondrocytes and cartilage explants with an IC50 value of approximately 1 microM. To inhibit NO production, SB 203580 had to be present in cartilage explant cultures during the first 8 h of IL-1 stimulation, and activity was lost when it was added 24 h following IL-1. SB 203580 did not inhibit iNOS activity, as measured by the conversion of arginine to citrulline, when added directly to cultures where the enzyme had already been induced, but had to be present during the induction period. Using a 372-bp probe for bovine iNOS we demonstrated inhibition of IL-1-induced mRNA by SB 203580 at both 4 and 24 h following IL-1 treatment. The iNOS mRNA levels were consistent with NO levels in 24-h cell culture supernatants of the IL-1-stimulated bovine chondrocytes used to obtain the RNA.

OBJECTIVE: To examine the performance of ultrasound (US) for the diagnosis of gout using the presence of monosodium urate monohydrate (MSU) crystals as the gold standard. METHODS: We analyzed data from the Study for Updated Gout Classification Criteria (SUGAR), a large, multicenter observational cross-sectional study of consecutive subjects with at least 1 swollen joint who conceivably may have gout. All subjects underwent arthrocentesis; cases were subjects with confirmed MSU crystals. Rheumatologists or radiologists who were blinded with regard to the results of the MSU crystal analysis performed US on 1 or more clinically affected joints. US findings of interest were double contour sign, tophus, and snowstorm appearance. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Multivariable logistic regression models were used to examine factors associated with positive US results among subjects with gout. RESULTS: US was performed in 824 subjects (416 cases and 408 controls). The sensitivity, specificity, PPV, and NPV for the presence of any 1 of the features were 76.9%, 84.3%, 83.3%, and 78.2%, respectively. Sensitivity was higher among subjects with a disease duration of ≥2 years and among subjects with subcutaneous nodules on examination (suspected tophus). Associations with a positive US finding included suspected clinical tophus (odds ratio [OR] 4.77 [95% confidence interval (95% CI) 2.23-10.21]), any abnormality on plain radiography (OR 4.68 [95% CI 2.68-8.17]), and serum urate level (OR 1.31 [95% CI 1.06-1.62]). CONCLUSION: US features of MSU crystal deposition had high specificity and high PPV but more limited sensitivity for early gout. The specificity remained high in subjects with early disease and without clinical signs of tophi.

OBJECTIVE: Wnt signaling is a master regulator of joint homeostasis, but its role in osteoarthritis (OA) remains unclear. This study was undertaken to characterize the activation of Wnt/β-catenin in knee joints of mice with OA and to assess how inhibiting this pathway in bone could affect cartilage. METHODS: OA was induced by partial meniscectomy in Topgal mice and in transgenic mice overexpressing Dkk-1 under the control of the 2.3-kb Col1a1 promoter (Col1a1-Dkk-1-Tg mice). Wnt/β-catenin activation was assessed by X-Gal staining at baseline and at weeks 4, 6, and 9. Cartilage and bone damage was analyzed in Col1a1-Dkk-1-Tg mice with OA at week 6. Primary chondrocytes and cartilage explants were used to assess the effect of Dkk-1 on cartilage catabolism. RESULTS: In meniscectomized Topgal mice, Wnt was mainly activated in osteocytes from the subchondral bone at week 6 after OA induction, as well as in osteophytes and synovium at week 4. Chondrocytes from damaged zones expressed X-Gal from week 4. Dkk-1 expression was high in chondrocytes in control mouse knees (mean ± SEM 84.2 ± 3.1%) but decreased greatly in knees of meniscectomized mice from week 4 (mean ± SEM 14.4 ± 3.8%). The OA score was lower in meniscectomized Col1a1-Dkk-1-Tg mice at week 6 compared with wild-type mice (5.1 ± 0.6 versus 8.4 ± 0.6; P = 0.002). Subchondral bone fraction and osteophyte volume were decreased. However, cartilage explants from Col1a1-Dkk-1-Tg mice showed proteoglycan loss and increased NITEGE expression. Expression of vascular endothelial growth factor (VEGF) was reduced in osteoblasts from Col1a1-Dkk-1-Tg mice, thereby decreasing expression of messenger RNA for matrix metalloproteinases in chondrocytes. CONCLUSION: Wnt activation in OA affects the whole joint, particularly bone. Selective inhibition of this pathway in bone by Dkk-1 decreased OA severity through VEGF inhibition.

PURPOSE OF REVIEW: Increasing evidence show that bone is a key factor in the development of osteoarthritis. This article reviews the latest results of basic and clinical research on the role of the subchondral bone in osteoarthritis. RECENT FINDINGS: Early changes in the subchondral bone can predict subsequent symptoms or disease structural progression. New tools may help clinicians to stratify different osteoarthritis phenotypes with regards to bone remodeling status. SUMMARY: The involvement of bone in osteoarthritis has long been thought to be secondary to cartilage damage as an adaptation of the joint. Recent clinical studies with MRI have demonstrated that bone changes could be observed in early stages of the disease, even preceding cartilage lesions. Moreover, there is clear evidence of an association between subchondral bone mineral density and osteoarthritis. The level of bone remodeling plays a critical role under mechanical loading conditions as demonstrated by consistent experimental studies. Yet new clinical biomarkers are being developed to assess the bone phenotype of osteoarthritic patients. This stratification strategy is likely to better identify groups of patients who would benefit from bone-acting drugs to decrease disease progression and improve pain and disability.

Low oxygen tension (hypoxia) regulates chondrocyte differentiation and metabolism. Hypoxia-inducible factor 1α (HIF1α) is a crucial hypoxic factor for chondrocyte growth and survival during development. The major metalloproteinase matrix metalloproteinase 13 (MMP13) is also associated with chondrocyte hypertrophy in adult articular cartilage, the lack of which protects from cartilage degradation and osteoarthritis (OA) in mice. MMP13 is up-regulated by the Wnt/β-catenin signaling, a pathway involved in chondrocyte catabolism and OA. We studied the role of HIF1α in regulating Wnt signaling in cartilage and OA. We used mice with conditional knockout of Hif1α (∆Hif1α(chon)) with joint instability. Specific loss of HIF1α exacerbated MMP13 expression and cartilage destruction. Analysis of Wnt signaling in hypoxic chondrocytes showed that HIF1α lowered transcription factor 4 (TCF4)-β-catenin transcriptional activity and inhibited MMP13 expression. Indeed, HIF1α interacting with β-catenin displaced TCF4 from MMP13 regulatory sequences. Finally, ΔHif1α(chon) mice with OA that were injected intraarticularly with PKF118-310, an inhibitor of TCF4-β-catenin interaction, showed less cartilage degradation and reduced MMP13 expression in cartilage. Therefore, HIF1α-β-catenin interaction is a negative regulator of Wnt signaling and MMP13 transcription, thus reducing catabolism in OA. Our study contributes to the understanding of the role of HIF1α in OA and highlights the HIF1α-β-catenin interaction, thus providing new insights into the impact of hypoxia in articular cartilage.

OBJECTIVE: The language currently used to describe gout lacks standardization. The aim of this project was to develop a consensus statement on the labels and definitions used to describe the basic disease elements of gout. METHODS: Experts in gout (n = 130) were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach consensus on the labeling and definitions for the basic disease elements of gout. Disease elements and labels in current use were derived from a content analysis of the contemporary medical literature, and the results of this analysis were used for item selection in the Delphi exercise and face-to-face consensus meeting. RESULTS: There were 51 respondents to the Delphi exercise and 30 attendees at the face-to-face meeting. Consensus agreement (≥80%) was achieved for the labels of 8 disease elements through the Delphi exercise; the remaining 3 labels reached consensus agreement through the face-to-face consensus meeting. The agreed labels were monosodium urate crystals, urate, hyperuric(a)emia, tophus, subcutaneous tophus, gout flare, intercritical gout, chronic gouty arthritis, imaging evidence of monosodium urate crystal deposition, gouty bone erosion, and podagra. Participants at the face-to-face meeting achieved consensus agreement for the definitions of all 11 elements and a recommendation that the label "chronic gout" should not be used. CONCLUSION: Consensus agreement was achieved for the labels and definitions of 11 elements representing the fundamental components of gout etiology, pathophysiology, and clinical presentation. The Gout, Hyperuricemia, and Crystal-Associated Disease Network recommends the use of these labels when describing the basic disease elements of gout.

INTRODUCTION: Sclerostin is a Wnt inhibitor produced by osteocytes that regulates bone formation. Because bone tissue contributes to the development of osteoarthritis (OA), we investigated the role of sclerostin in bone and cartilage in a joint instability model in mice. METHODS: Ten-week-old SOST-knockout (SOST-KO) and wild-type (WT) mice underwent destabilization of the medial meniscus (DMM). We measured bone volume at the medial femoral condyle and osteophyte volume and determined the OA score and expression of matrix proteins. Primary murine chondrocytes were cultured with Wnt3a and sclerostin to assess the expression of matrix proteins, proteoglycan release and glycosaminoglycan accumulation. RESULTS: Sclerostin was expressed in calcified cartilage of WT mice with OA. In SOST-KO mice, cartilage was preserved despite high bone volume. However, SOST-KO mice with DMM had a high OA score, with increased expression of aggrecanases and type X collagen. Moreover, SOST-KO mice with OA showed disrupted anabolic-catabolic balance and cartilage damage. In primary chondrocytes, sclerostin addition abolished Wnt3a-increased expression of a disintegrin and metalloproteinase with thrombospondin motifs, matrix metalloproteinases and type X collagen by inhibiting the canonical Wnt pathway. Moreover, sclerostin inhibited Wnt-phosphorylated c-Jun N-terminal kinase (JNK) and rescued the expression of anabolic genes. Furthermore, sclerostin treatment inhibited both Wnt canonical and non-canonical JNK pathways in chondrocytes, thus preserving metabolism. CONCLUSION: Sclerostin may play an important role in maintaining cartilage integrity in OA.